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AJHG:新型遗传测序技术或可帮助科学家开发出先天性高胰岛素血症的新疗法

  1. AJHG
  2. 先天性高胰岛素血症
  3. 疗法
  4. 遗传测序

来源:生物谷 2012-12-29 00:24

2012年12月29日 讯 /生物谷BIOON/ --先天性的高胰岛素血症是一种遗传病症,是由于个体处于婴儿期其胰腺分泌了过多的胰岛素导致的病症,在50,000个新生儿中大约影响1一个新生儿的健康,而且在某些病症中,需要进行外科手术遗传全部或者部分胰腺才能够治疗该疾病。

2012年12月29日 讯 /生物谷BIOON/ --先天性的高胰岛素血症是一种遗传病症,是由于个体处于婴儿期其胰腺分泌了过多的胰岛素导致的病症,在50,000个新生儿中大约影响1一个新生儿的健康,而且在某些病症中,需要进行外科手术遗传全部或者部分胰腺才能够治疗该疾病。

近日,刊登在国际杂志The American Journal of Human Genetics上的研究报告中,来自埃克塞特大学医学院的研究者首次使用新的遗传测序技术进行测序,旨在寻找引发高胰岛素血症的基因突变。原来的技术仅限于对部分可编码区域进行测序,这就使得一些引发疾病的突变会被忽视。

文章中,研究者使用了Illumina遗传测序技术,发现了许多新型的引发高胰岛素血症的突变。结果就是许多高胰岛素血症的新生婴儿将需要较少的调查研究,因为最新的技术针对那些只有一次遗传测试的个体需要进行深入研究来确定每一个新生儿患病的程度。同样医生们也需要了解更多的信息来告知患病婴儿的家属需要移除婴儿多少胰腺。

大约50%的先天性的高胰岛素血症患者需要进行手术治疗,而且患者中有一半都需要全部切除胰腺,移除患者的整个胰腺将会增加其患糖尿病的风险,但是长期的高胰岛素血症会导致个体发生不能挽回的脑部损伤。

研究者Sarah Flanagan说,这项新型技术非常重要而且令人兴奋,因为其帮助我们完整地调查了个体患病的遗传密码信息,帮助我们鉴别出了引发疾病的遗传突变,对于我们开发新型的疗法或者干预措施提供了帮助和希望。(生物谷Bioon.com)

Next-Generation Sequencing Reveals Deep Intronic Cryptic ABCC8 and HADH Splicing Founder Mutations Causing Hyperinsulinism by Pseudoexon Activation

Sarah E. Flanagan1, Weijia Xie1, Richard Caswell1, Annet Damhuis2, Christine Vianey-Saban3, Teoman Akcay4, Feyza Darendeliler5, Firdevs Bas5, Ayla Guven6, Zeynep Siklar7, Gonul Ocal7, Merih Berberoglu7, Nuala Murphy8, Maureen OSullivan9, 10, Andrew Green11, 12, Peter E. Clayton13, Indraneel Banerjee13, 14, Peter T. Clayton15, Khalid Hussain16, 17, Michael N. Weedon1 and Sian Ellard

Next-generation sequencing (NGS) enables analysis of the human genome on a scale previously unachievable by Sanger sequencing. Exome sequencing of the coding regions and conserved splice sites has been very successful in the identification of disease-causing mutations, and targeting of these regions has extended clinical diagnostic testing from analysis of fewer than ten genes per phenotype to more than 100. Noncoding mutations have been less extensively studied despite evidence from mRNA analysis for the existence of deep intronic mutations in >20 genes. We investigated individuals with hyperinsulinaemic hypoglycaemia and biochemical or genetic evidence to suggest noncoding mutations by using NGS to analyze the entire genomic regions of ABCC8 (117 kb) and HADH (94 kb) from overlapping 10 kb PCR amplicons. Two deep intronic mutations, c.1333-1013A>G in ABCC8 and c.636+471G>T HADH, were identified. Both are predicted to create a cryptic splice donor site and an out-of-frame pseudoexon. Sequence analysis of mRNA from affected individuals fibroblasts or lymphoblastoid cells confirmed mutant transcripts with pseudoexon inclusion and premature termination codons. Testing of additional individuals showed that these are founder mutations in the Irish and Turkish populations, accounting for 14% of focal hyperinsulinism cases and 32% of subjects with HADH mutations in our cohort. The identification of deep intronic mutations has previously focused on the detection of aberrant mRNA transcripts in a subset of disorders for which RNA is readily obtained from the target tissue or ectopically expressed at sufficient levels. Our approach of using NGS to analyze the entire genomic DNA sequence is applicable to any disease.

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